Testosterone is the principal androgenic hormone, playing a key role in the physiology of the normal male, essential for muscle mass, bone mass, libido, potency and spermatogenesis. About 6 mg of testosterone is produced per day in the testes. In females small amounts of testosterone are essential for sexual function, bone density, muscle mass, cognitive function and mood.
Testosterone (T) is metabolized to dihydrotestosterone (DHT) by the enzyme 5-alpha-reductase. In normal men the DHT/T ratio is about 0.10-0.15. Also DHT/T ratios between 0.05-0.33 have been reported as normal. Diver M. J. Ann Clin Biochem 2006; 43: 3-12 and Diver M. J. et al. Clin. Endocrinology 2003; 58:710-717 reported that total serum testosterone displays a circadian rhythm with the highest concentrations found in the morning and the lowest in the evening, with a decrease of at least 43% from peak to nadir testosterone level.
Normal testosterone serum levels in males are approximately between 10-35 nmol/liter. According to the laboratory values used in the USA this is 300-1000 ng/dl (3-10 ng/ml).
In females only very small amounts of testosterone are produced, with normal values varying between 0.2-3 nmol/L (=6-90 ng/dl). As a reference: 1 ng/ml testosterone=3.47 nmol/L, 1 nmol/L testosterone=0.288 ng/ml, and 1 ng/dl testosterone=0.0347 nmol/L.
Testosterone is secreted in healthy men in a pulsatile pattern, with a frequency of about 13 pulses per day. Maximum pulse levels may reach values of 31.5 nmol/L (J. Clin. Endocrin. Metab. 1987; 65: 929-941).
Hypogonadism is a term indicating a decreased function of the gonads (testes, ovaries). In male hypogonadism, resulting from a variety of pathophysiological conditions, the production of testosterone in the testes is insufficient, i.e. serum testosterone levels are below 10 nmol/l (below 300 ng/dl). Low testosterone levels are linked with a number of physiological changes, such as diminished interest in sex, impotence, reduced lean body mass, decreased bone density, lowered mood and energy levels. Even a link between low testosterone in elder men and a higher mortality has been suggested in recent studies.
Hypogonadism is classified into one of three types. In primary hypogonadism low serum testosterone concentrations are caused by testicular failure. In secondary hypogonadism the testes do not receive the correct signal from some brain hormones to produce testosterone.
The third cause of hypogonadism is age-related. Men experience a slow but continuous decline in average serum testosterone levels after approximately age 20 to 30 years. Also the serum concentration of SHBG (sex hormone-binding globulin) increases as men age, with the consequence that the fall in bioavailable and free testosterone is greater than the total testosterone levels. As men age, the circadian rhythm (diurnal variation) of testosterone concentration may disappear. Testosterone deficiency in older men may lead to sexual dysfunction, decreased libido, loss of muscle mass, decreased bone density, depressed mood, and decreased cognitive function. This physiological condition is called geriatric hypogonadism, or “male menopause.”
In current therapy, by oral, parenteral, transdermal or buccal administration, very high doses of testosterone are used.
Oral therapy of testosterone lacks effectiveness because testosterone is metabolized extensively during the first passage of the liver before reaching the systemic blood circulation (first-pass effect). Intramuscular injections of testosterone esters are widely used, but local pain, tolerability and the unphysiologically high levels in the first days/weeks after injection are severe drawbacks of this treatment. Local pain is attributed to the large volumes injected, while the required help of health care professionals makes injections inconvenient and expensive. These drawbacks are also valid for implanted pellets.
Transdermal administration, using patches and gels, has the advantage that the first-pass effect is avoided and the treatment is not painful. Also the risk of too high testosterone levels associated with injections is reduced. Local skin reactions common with patches and other drawbacks such as dose inflexibility and visibility, lead to a high discontinuation rate however. All gels, currently prescribed for hypogonadal men, contain about 50 mg testosterone per dose unit of which only a low percentage is absorbed actually after permeation through the skin. A large part of the testosterone remains on the skin, with the potential risk of transfer to the skin of other persons (children, women) when direct skin-to-skin contact is made. The amount of testosterone not absorbed disappears in the environment, making these formulations not environmental-friendly products. A common side effect is local skin irritation, probably because of the very high ethanol content of such formulations.
Also available are buccal tablets (Striant™). They adhere to the gum and inner cheek, contain 30 mg testosterone per tablet and have to be administered every 12 hours. However, also this product also has severe drawbacks. Two times 30 mg per day, in total 60 mg per 24 hrs, is a very high dose of testosterone, keeping in mind that a healthy male produces only 6 mg testosterone per day.
WO 97/38663 discloses buccal spray and bite capsules using a non-polar solvent such as miglyol. Illustrated are compositions delivering 4 mg testosterone/activation for the spray (example 3) and 5 mg per bite capsule (example 7).
U.S. Pat. No. 6,110,486 discloses a similar buccal spray and bite capsule for biologically active compounds such as testosterone. The spray formulations contain 1-20% of active ingredient in a polar solvent such as a low molecular weight polyethylene glycol, alcohols, polyol, and also water. Illustrated are spray formulations that deliver 3 mg testosterone/activation and in particular such formulations containing 65% of polyethylene glycol. The latter has a characteristic odour and a bitter, burning taste in the mouth, making formulations based on these ingredients poorly tolerable, in particular for frequent use.
US 2005/0180923 discloses buccal sprays and bite capsules for biologically active compounds such as testosterone. The spray formulations use a polar or non-polar solvent and may contain a propellant.
U.S. Pat. No. 4,596,795 teaches that rapid and complete dissolution of testosterone preparations in the mouth, achieved by hydrophilic cyclodextrin derivatives, enables an effective absorption of testosterone into the systemic circulation of men. Only testosterone complexes of hydroxypropyl-beta-cyclodextrin (HPBCD) and poly-beta-cyclodextrin were found to be effective, while beta-cyclodextrin was found ineffective. Also heptakis-2,6-O-dimethyl-beta-cyclodextrin complexes appeared to have only a marginal effect on the absorption of testosterone.
Further studies, using tablets of sublingual testosterone complexed with HPBCD, showed that at a 5 mg dose, a maximal concentration (Cmax) of testosterone (85.4 nmol/L) was achieved in 20 min (Stuenkel, et al., J. Clin. Endocrinol. Metabolism 1991; 72: 1054-1059). In other studies using 5 mg Testosterone-HPBCD sublingual tablets, Wang et al (J. Clin. Endocrinol. Metabolism 1996; 81: 3654-3662) reported Cmax levels of 45 nmol/L 30 minutes post-dose, and Salehian, et al. (J. Clin. Endocrinol. Metabolism 1995; 80: 3567-3575) measured peak levels of 35-45 nmol/L, 20 minutes after sublingual doses of 2.5 and 5 mg.
EP 1872774 teaches a composition for oral transmucosal administration and its uses. It comprises a water soluble complex of testosterone and a cyclodextrin derivative, the amount of the testosterone in the composition being 0.01-7 mg. Illustrated is a filtration paper disk for sublingual use containing 5 mg testosterone in a HPBCD complex. No differentiation between cyclodextrins is made, although U.S. Pat. No. 4,596,795 discloses, as stated above, that beta-cyclodextrin and 2,6-dimethylated-beta-cyclodextrin complexes with testosterone lack effectiveness.
In 2,6-O-dimethyl-beta-cyclodextrin the 2- and 6-hydroxy groups of the glucopyranoside units are methylated. In the present invention randomly methylated-beta-cyclodextrin, also called RAMEB, is used, in which about 1.5-2.0 of the hydroxy groups of the glucopyranoside units are methylated. RAMEB, commercially available as Cavasol W7M, is much easier to produce, while the binding constants with drugs and the solubility in water are the same as 2,6-O-dimethyl-beta-cyclodextrin (Marttin, E. et al; J. Drug Targeting 1998:6:17-36).
WO 90/01320 describes complexes of beta-cyclodextrins, branched with anhydroglucose units, with a steroid, including testosterone, having increased water-solubility.
WO 2005/044273 describes nasal sex hormone formulations comprising a lipophilic component and an emulsifier in an amount sufficient to generate an in situ emulsion. According to the website clinicaltrials.gov, NCT00975650 one such formulation is in development, comprising 2% testosterone in castor oil, a surfactant, and colloidal silicon dioxide, using doses of 8, 11 and 14 mg testosterone intranasally.
WO 00/21503 also discloses a nasal composition of testosterone comprising a 20 liter aqueous solution containing 43.92 g testosterone and 418.92 g RAMEB, which corresponds to a nasal aqueous solution of 2.2 mg testosterone/ml in 2.1% RAMEB (DS=degree of substitution 1.7). No further information is given.
A therapeutic reason to individualise testosterone suppletion therapy is the expectation that in the near future increasing knowledge of polymorphism of the androgen receptor and individual metabolic characteristics will prove to be relevant in establishing target testosterone levels in individual patients, because patients with insensitive receptors, for instance, need higher normal serum levels than normal, and slow metabolisers require a lower testosterone dose than fast metabolisers.
None of the current treatment approaches is satisfactory in that very high dosages are used and obviously required to get a few mg testosterone actually absorbed in the general circulation. The amount of testosterone in the prior art compositions is very high, several times higher, and often 5-10 times higher than disclosed in the present invention.
None of the prior art compositions disclose a controlled increase proportional to the amount of testosterone administered by a single or multiple oromucosal administration of a low dose testosterone.
Neither does the prior art teach titrating (adjusting and selecting) the required testosterone dose to control the testosterone serum level to keep it between normal physiological values, without overdosing. No therapy has been described that offers the possibility to adapt the dose and dosage frequency each day.
It is an object of this invention to provide a dose and dosage frequency that is tailor-made per individual patient, thereby mimicking the circadian rhythm and physiological pulsatile secretion of testosterone and keeping the testosterone levels over 24 hrs within the range of 10-35 nmol/L (in male patients).
A further object is to provide low dose formulations that give sufficiently high testosterone levels. This contrary to currently available treatment options, which use very high dosages, needed to get a few mg testosterone actually absorbed per day into the systemic circulation.
Another object is to provide a controlled increase of testosterone levels proportional to the amount of testosterone administered.